Description of Research
Our lab is interested in the biology of human aging and cancer, and we are focusing particularly on how they are influenced by telomere maintenance and dysfunction. Telomeres are the structures that cap the ends of chromosomes, and this location makes them critical for genome stability as well as particularly susceptible themselves to a variety of insults including oxidative damage, exonucleolytic attack, and inappropriate processing by recombination factors.

One focus of the lab is to investigate mechanisms of telomere maintenance. We have identified roles for the RecQ family DNA helicases in coordinating recombination-dependent mechanisms that maintain telomeres. This family of helicases includes those that are deficient in the Werner and Bloom syndromes, which are diseases characterized by premature aging and elevated rates of cancer. Our findings in mice and yeast have helped establish telomere defects as an important cause of the clinical phenotypes observed in these syndromes. More recently, we have also begun exploring roles for chromatin regulatory factors, including SUMO modifiers and regulators of histone acetylation, in telomere maintenance. We hope that by better understanding how RecQ helicases and chromatin factors maintain telomeres, new methods for preserving telomere function in normal tissues and for disrupting telomere function in malignancies may be developed.

A second focus of the lab is to investigate the biology of G-quadruplexes, which are four-stranded DNA structures formed by G-rich sequences like telomeres. The RecQ family of helicases, including WRN and BLM, are particularly adept at unwinding G-quadruplexes. Recently, we have obtained evidence that G-quadruplexes regulate telomere capping, cell senescence, DNA recombination and transcription in vivo. Cell biologic, bioinformatic and structural approaches to understanding G-quadruplex function are being pursued.

A third focus of the lab is to use a mouse model lacking telomerase to learn more about the mechanisms by which telomere dysfunction contributes to age-related pathology. We are investigating how transplantation of normal bone marrow and manipulation of the Wnt pathway rescues this and other degenerative phenotypes in these mice.

A fourth interest of the lab is the measurement in human clinical specimens of telomere lengths and capping, telomerase activity, chromatin regulators, and cell senescence. We are particularly interested in understanding how these factors contribute to age-related neurodegenerative diseases and the success of transplanted tissues.